Class II MHC (Ia) gene products play critical roles in a variety of T and B lymphocyte responses. A combination of immunological, molecular genetic, and biochemical appraoches is being used to study the relationship between Ia structure and function. The defect in expression in most cases of "allelically mismatched" Alpha and Beta chains lies in the failure of assembled heterodimers to efficiently exit the endoplasmic reticulum. Many of these poorly transported dimers can be "rescued" at least in part by co-expression of adequate amounts of the non-MHC encoded invariant chain, a process that is affected by the intracellular localization signal(s) on the cytoplasmic tail of the invariant chain. This same region also controls the efficiency of class II peptide acquisition. In vitro experiments with purified class II demonstrate that conformation is dictated by whether or not appropriate peptides are bound by the NH2-terminal domains of the AlphaBeta dimer, and that the most stable structure of class II includes such bound peptides. The use of direct peptide binding techniques, together with transfectants expressing mutant class II molecules, has permitted the definition of a local peptide binding subregion in the murine I-E molecule, and the role of specific allelically polymorphic residues in controlling the quantitative and qualitative binding of peptide to this molecule. Finally, mutational analysis has begun to define the site(s) of interaction of Ia with CD4, a molecule that functions as a co-receptor along with the T cell receptor in recognition of class II molecules during T cell activation. Together with the studies on class II folding, transport, and control of peptide binding by the polymorphic domain, these experiments will provide new insight into the molecular mechanisms involved in antigen recognition by and activation of T lymphocytes.